Multicenter Study

. 2022 Apr;7(4):342-352.

doi: 10.1016/S2468-1253(22)00005-X. Epub 2022 Feb 4.

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study

James L Alexander¹, Nicholas A Kennedy², Hajir Ibraheim¹, Sulak Anandabaskaran³, Aamir Saifuddin³, Rocio Castro Seoane⁴, Zhigang Liu⁴, Rachel Nice⁵, Claire Bewshea⁶, Andrea D'Mello⁷, Laura Constable⁴, Gareth R Jones⁸, Sharmili Balarajah¹, Francesca Fiorentino⁹, Shaji Sebastian¹⁰, Peter M Irving¹¹, Lucy C Hicks¹, Horace R T Williams¹, Alexandra J Kent¹², Rachel Linger¹³, Miles Parkes¹⁴, Klaartje Kok¹⁵, Kamal V Patel¹⁶, Julian P Teare¹, Daniel M Altmann¹⁷, Rosemary J Boyton¹⁸, James R Goodhand², Ailsa L Hart¹⁹, Charlie W Lees⁸, Tariq Ahmad², Nick Powell²⁰; VIP study investigators

Collaborators, Affiliations

Affiliations

¹ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Department of Gastroenterology, Imperial College Healthcare NHS Trust, London, UK.
² Department of Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
³ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Department of Gastroenterology, St Mark's Hospital and Academic Institute, London, UK.
⁴ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
⁵ Department of Clinical Chemistry, Biochemistry-Exeter Clinical Laboratory International, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
⁶ Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
⁷ Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London, UK.
⁸ Department of Gastroenterology, Western General Hospital, NHS Lothian, Edinburgh, UK; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
⁹ Department of Surgery and Cancer, Imperial College London, London, UK; Nightingale-Saunders Clinical Trials and Epidemiology Unit, King's Clinical Trials Unit, King's College London, London, UK.
¹⁰ Department of Gastroenterology, Hull University Teaching Hospitals NHS Trust, Hull, UK; Hull York Medical School, University of Hull, Hull, UK.
¹¹ School of Immunology and Microbial Sciences, King's College London, London, UK; Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹² Department of Gastroenterology, King's College Hospital, London, UK.
¹³ The NIHR Bioresource, University of Cambridge, Cambridge, UK.
¹⁴ The NIHR Bioresource, University of Cambridge, Cambridge, UK; Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
¹⁵ Department of Gastroenterology, Bart's Health NHS Trust, London, UK.
¹⁶ Department of Gastroenterology, St George's Hospital NHS Trust, London, UK.
¹⁷ Department of Immunology and Inflammation, Imperial College London, London, UK.
¹⁸ Department of Infectious Disease, Imperial College London, London, UK.
¹⁹ Department of Gastroenterology, St Mark's Hospital and Academic Institute, London, UK.
²⁰ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Department of Gastroenterology, Imperial College Healthcare NHS Trust, London, UK. Electronic address: nicholas.powell@imperial.ac.uk.

PMID: 35123676
PMCID: PMC8813209
DOI: 10.1016/S2468-1253(22)00005-X

Multicenter Study

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study

James L Alexander et al. Lancet Gastroenterol Hepatol. 2022 Apr.

. 2022 Apr;7(4):342-352.

doi: 10.1016/S2468-1253(22)00005-X. Epub 2022 Feb 4.

Authors

Affiliations

¹ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Department of Gastroenterology, Imperial College Healthcare NHS Trust, London, UK.
² Department of Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
³ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Department of Gastroenterology, St Mark's Hospital and Academic Institute, London, UK.
⁴ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.
⁵ Department of Clinical Chemistry, Biochemistry-Exeter Clinical Laboratory International, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
⁶ Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.
⁷ Division of Medicine and Integrated Care, Imperial College Healthcare NHS Trust, London, UK.
⁸ Department of Gastroenterology, Western General Hospital, NHS Lothian, Edinburgh, UK; Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
⁹ Department of Surgery and Cancer, Imperial College London, London, UK; Nightingale-Saunders Clinical Trials and Epidemiology Unit, King's Clinical Trials Unit, King's College London, London, UK.
¹⁰ Department of Gastroenterology, Hull University Teaching Hospitals NHS Trust, Hull, UK; Hull York Medical School, University of Hull, Hull, UK.
¹¹ School of Immunology and Microbial Sciences, King's College London, London, UK; Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
¹² Department of Gastroenterology, King's College Hospital, London, UK.
¹³ The NIHR Bioresource, University of Cambridge, Cambridge, UK.
¹⁴ The NIHR Bioresource, University of Cambridge, Cambridge, UK; Department of Gastroenterology, Cambridge University Hospitals NHS Trust, Cambridge, UK.
¹⁵ Department of Gastroenterology, Bart's Health NHS Trust, London, UK.
¹⁶ Department of Gastroenterology, St George's Hospital NHS Trust, London, UK.
¹⁷ Department of Immunology and Inflammation, Imperial College London, London, UK.
¹⁸ Department of Infectious Disease, Imperial College London, London, UK.
¹⁹ Department of Gastroenterology, St Mark's Hospital and Academic Institute, London, UK.
²⁰ Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK; Department of Gastroenterology, Imperial College Healthcare NHS Trust, London, UK. Electronic address: nicholas.powell@imperial.ac.uk.

PMID: 35123676
PMCID: PMC8813209
DOI: 10.1016/S2468-1253(22)00005-X

Abstract

Background: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs.

Methods: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing.

Findings: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations.

Interpretation: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised.

Funding: Pfizer.

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Conflict of interest statement

Declaration of interests JLA reports sponsorship from Vifor Pharma for accommodation and travel to the British Society of Gastroenterology annual meeting 2019, outside the submitted work. NAK reports grants from AbbVie, Biogen, Celgene, Celtrion, Galapagos, MSD, Napp, Pfizer, Pharmacosmos, Roche, and Takeda; consulting fees from Amgen, Bristol Myers Squibb, Falk, Janssen, Mylan, Pharmacosmos, Galapagos, Takeda, and Tillotts; personal fees from Allergan, Celltrion, Falk, Ferring, Janssen, Pharmacosmos, Takeda, Tilllotts, and Galapagos; and support for attending meetings from AbbVie, Falk, and Janssen, outside the submitted work. AS has received travel expense support from Janssen. SS reports grants from Takeda, AbbVie, Tillots Pharma, Janssen, Pfizer, and Biogen, and personal fees from Takeda, AbbVie, Janssen, Pharmacocosmos, Biogen, Pfizer, Tillots Pharma, and Falk Pharma, outside the submitted work. ALH reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, AZ, Atlantic, Bristol Myers Squibb, Celltrion, Falk, Galapogos, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire, and Takeda; participation on the Global Steering Committee for Genentech; support for attending meetings from AbbVie, Takeda, and Janssen; and participation on a data safety monitoring board or advisory board for AbbVie, AZ, Atlantic, Bristol Myers Squibb, Galapogos, Janssen, Pfizer, and Takeda. PMI reports grants from Celltrion, Takeda, MSD, Pfizer, and Galapagos, and personal fees from Celltrion, Takeda, Pfizer, Galapagos, Gilead, AbbVie, Janssen, Bristol Myers Squibb, Lilly, and Arena, outside the submitted work. MP receives unrestricted educational grants from Pfizer for genetic analyses to support the IBD BioResource and speaker fees from Janssen. GRJ has received grants from the Wellcome Trust and ECCO; speaker fees from Takeda, Ferring, and Janssen; and support for attending meetings or travel from Ferring. KK reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen and Ferring; support for attending meetings or travel from Janssen and Takeda; and participation on a data safety monitoring board or advisory board for Janssen and PredictImmune. KVP reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie, DrFalk, Janssen, PreddictImmune, and Takeda; support for attending meetings or travel from AbbVie, Ferring, Janssen, and Tillots; and participation on a data safety monitoring board or advisory board for AbbVie, Galapagos, and Janssen. AJK reports consulting fees from Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer and Takeda; support for attending meetings or travel from Janssen, Tillots, and Norgine; and participation on a data safety monitoring board or advisory board for AbbVie. LCH reports support for attending meetings or travel from AbbVie. CWL reports a Future Leaders Fellow award from UK Research and Innovation; personal consulting fees from Galapagos, AbbVie, Takeda, Pfizer, Janssen, and Iterative Scopes; institutional consulting fees from Trellus Health; personal fees from Galapagos, AbbVie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresnius Kabi, Ferring, and Dr Falk; and support for attending meetings from Galapagos, AbbVie, Takeda, Pfizer, Janssen, GSK, Gilead, Fresnius Kabi, Ferring, and Dr Falk. RJB and DMA are members of the Global T cell Expert Consortium and have consulted for Oxford Immunotec outside the submitted work. JRG reports grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, and Galapagos, and non-financial support from Immundiagnostik, during the conduct of the study. TA reports grant funding from Pfizer to his institution to deliver this study; grants from Celltrion, Roche, Takeda, Biogen, and Galapagos; and honoraria for lectures from Takeda and Roche, outside the submitted work. NP is the principal investigator on the research grant from Pfizer that helped to fund the VIP study; has received research grants from Bristol Myers Squibb outside the submitted work; reports personal fees from Takeda, Janssen, Pfizer, Bristol Myers Squibb, AbbVie, Roche, Lilly, Allergan, and Celgene, outside the submitted work; and has served as a speaker or advisory board member for AbbVie, Allergan, Bristol Myers Squibb, Celgene, Falk, Ferring, Janssen, Pfizer, Tillotts, Takeda, and Vifor Pharma. All other authors declare no competing interests.

Figures

**Figure 1**
Anti-SARS-CoV-2 spike protein antibody concentrations in people without evidence of previous infection (A) Multivariable model, adjusted for vaccine type and age, showing the exponentiated coefficients of linear regression models of log10-transformed concentrations of anti-SARS-CoV-2 spike protein antibodies stratified by study treatment group. Results are for individuals without evidence of previous infection. The values shown represent the geometric mean ratios of antibody concentrations associated with each variable. (B) Anti-SARS-CoV-2 spike protein antibody concentration stratified by study treatment group. The longer black bar represents the geometric mean and the shorter black bars represent 1 geometric SD either side of the geometric mean.

**Figure 2**
Multivariable model showing exponentiated coefficients of linear regression models of log₁₀-transformed concentrations of anti-SARS-CoV-2 spike protein antibodies, adjusting for known confounders Results are for individuals without evidence of previous infection. The values shown represent the geometric mean ratios of antibody concentrations associated with each variable. Age was treated as a continuous variable in the analysis and its coefficient is expressed per decade.

**Figure 3**
Seroconversion after vaccination in people without evidence of previous SARS-CoV-2 infection (A) Proportion of participants who were seronegative, defined by an anti-SARS-CoV-2 spike protein antibody concentration of less than 15 U/mL. The circles represent the proportion estimates and the error bars represent 95% CIs on either side. (B) Proportion of participants with anti-SARS-CoV-2 spike protein antibody concentrations greater than 2 geometric SDs below the geometric mean of healthy control participants. The circles represent the proportion estimates and the error bars represent 95% CIs on either side.

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Comment in

Is the attenuated humoral response to COVID-19 vaccination in anti-TNF users relevant?
Chhibba T, Targownik LE. Chhibba T, et al. Lancet Gastroenterol Hepatol. 2022 Apr;7(4):280-282. doi: 10.1016/S2468-1253(22)00040-1. Epub 2022 Feb 4. Lancet Gastroenterol Hepatol. 2022. PMID: 35123675 Free PMC article. No abstract available.

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COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study

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COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study

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